Despite progress made in many areas, brain tumors remain an extraordinary challenge. Due to the inherent risks associated with surgical resection and radiotherapy, the aggressiveness of many CNS tumors, and the difficulty in delivering anticancer drugs to the brain, the prognosis for patients with many types of brain tu- mors remains grim. This challenge is particularly stark for tumors near critical structures, such as those near the skull base. While extraordinary advances have occurred in neurosurgery, the procedures are long, trau- matic, and pose significant risk to the patient. Radiosurgery is a noninvasive option, but it also has limitations and recurrence is also a major challenge. New and less invasive alternatives to existing procedures are des- perately needed. This study will test the combination of Transcranial Magnetic Resonance Imaging-Guided Focused Ultrasound (TcMRgFUS) ablation and a microbubble-based ultrasound contrast agent (USCA) for ablation of brain tumors. The addition of the USCA targets the ultrasound effects directly to the microvascu- lature and enables ablation of tissue without bulk heating, which allows dramatically lower ultrasound expo- sure levels. This approach enables the ablation of tumors without damage to surrounding structures even in challenging areas, such as the skull base. We are developing methods that allow this ablation method to be applied in a controlled manner to ablate tissue volumes at the skull base without damaging adjacent nerve structures. We will optimize the exposure levels to produce ablation with the lowest possible energy delivery in different tumor models. We will also perform tests in nonhuman primates using a clinical TcMRgFUS sys- tem to establish the safety of sonicating deep brain structures in a large-brained animal. Targets will be se- lected directly adjacent to the optic tract, so we can confirm that the ablation can be achieved without collat- eral damage to adjacent nerve structures. In parallel, we will develop a passive ultrasound imaging method suitable for transcranial use to monitor the cavitation exposures in real time. This type of ablation has only begun to be studied. The proposed work will obtain the translational data needed to demonstrate that fo- cused ultrasound is clinically feasible approach to brain tumor ablation, even in challenging areas such as the skull base. RELEVANCE (See Instructions): Skull-based tumors are an extraordinary challenge, and new, less-invasive technologies are needed. In this work, we will test the combination of Magnetic Resonance Imaging-guided focused ultrasound and a micro- bubble-based agent, which enables us to noninvasively ablate tissue volumes next to challenging brain re gions such as the skull base. PROJECT/PERFORIWANCE SITE(S) (if additional space is needed, use